Despite efficient suppression of plasma viremia in HIV-infected patients on cART, replication competent virus is still recoverable from a variety of anatomic sites and most notably quiescent memory CD4+ T lymphocytes. Although empirical evidence suggests latent HIV is present throughout the oral mucosae, the full spectrum of infected cells in the oral cavity is undefined, and the contribution of the unique anatomy of these tissues to the systemic viral reservoir is unknown. In addition to being a potential reservoir for HIV/SIV, the oral cavity is home to a wide range of normally benign pathogens that during co-infection induced immunosuppression are major sources of co-morbidities. Although the underlying mechanisms for emergence of opportunistic viruses are not entirely clear, oral complications of HIV disease are widespread even with successful ARV therapy. Natural killer (NK) cells provide rapid early responses to HIV/SIV infections and contribute substantially to disease modulation and vaccine protection. Traditionally, NK cells have been considered to be nonspecific components of innate immunity, but recent studies in mice have shown that NK cells can also demonstrate features of antigen-specific memory. We also now demonstrate for the first time evidence of NK cell memory in higher primates specifically against HIV and SIV antigens (Reeves et al., Nat Imm, 2015). In this innovative proposal we will utilize the SIV-co-infected macaque model to test the central hypothesis that NK cells distributed throughout the oral mucosae are a common critical component for modulation of reservoirs of SIV and opportunistic viral infections. Specifically we will: (1) Define and quantify SIV reservoirs in the oral mucosa during cART; (2) Evaluate mechanisms of innate and antigen-specific NK cell modulation of SIV replication and reservoir seeding in the oral mucosae; and (3) Explore the effects of NK cell depletion on SIV reservoirs and rhLCV and rhCMV co-infections. Application of these data could lead to future HIV/SIV vaccines, immunotherapeutics, or reservoir purging strategies that harness the potent antiviral potential of NK cells.